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Treatment of hemophilia

W Keith Hoots, MD
Amy D Shapiro, MD
Section Editors
Donald H Mahoney, Jr, MD
Lawrence LK Leung, MD
Deputy Editor
Jennifer S Tirnauer, MD


The hemophilic conditions are a group of related inherited bleeding disorders and include abnormalities of coagulation factors as well as platelet function; the most common of these disorders is von Willebrand disease. However, when the term "hemophilia" is used, it most often refers to one of the following two disorders:

Factor VIII deficiency (hemophilia A)

Factor IX deficiency (hemophilia B, Christmas disease)

The treatment of hemophilia A and B will be reviewed here [1,2]. Other topic reviews discuss the following issues in patients with hemophilia A and B:

Clinical manifestations – (See "Clinical manifestations and diagnosis of hemophilia".)


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  1. Berntorp E, Shapiro AD. Modern haemophilia care. Lancet 2012; 379:1447.
  2. Ljung RC, Knobe K. How to manage invasive procedures in children with haemophilia. Br J Haematol 2012; 157:519.
  3. Bolton-Maggs PH. Optimal haemophilia care versus the reality. Br J Haematol 2006; 132:671.
  4. Ljung R, Petrini P, Nilsson IM. Diagnostic symptoms of severe and moderate haemophilia A and B. A survey of 140 cases. Acta Paediatr Scand 1990; 79:196.
  5. Pollmann H, Richter H, Ringkamp H, Jürgens H. When are children diagnosed as having severe haemophilia and when do they start to bleed? A 10-year single-centre PUP study. Eur J Pediatr 1999; 158 Suppl 3:S166.
  6. Koch JA. Haemophilia in the newborn. A case report and literature review. S Afr Med J 1978; 53:721.
  7. Kavakli K, Kurugöl Z, Göksen D, Nisli G. Should hemophiliac patients be circumcised? Pediatr Hematol Oncol 2000; 17:149.
  8. Rosner F. Hemophilia in the Talmud and rabbinic writings. Ann Intern Med 1969; 70:833.
  9. Martinowitz U, Varon D, Jonas P, et al. Circumcision in hemophilia: the use of fibrin glue for local hemostasis. J Urol 1992; 148:855.
  10. Jones P. Management of haemophilia. Arch Dis Child 1984; 59:1010.
  11. Ross C, Goldenberg NA, Hund D, Manco-Johnson MJ. Athletic participation in severe hemophilia: bleeding and joint outcomes in children on prophylaxis. Pediatrics 2009; 124:1267.
  12. Gomis M, Querol F, Gallach JE, et al. Exercise and sport in the treatment of haemophilic patients: a systematic review. Haemophilia 2009; 15:43.
  13. Search for Publications, General Guides, and article "Exercises for people with hemophilia." www.wfh.org (Accessed on December 22, 2009).
  14. Search on "Exercise" and "Sports participation." www.hemophilia.org (Accessed on December 22, 2009).
  15. Soucie JM, Nuss R, Evatt B, et al. Mortality among males with hemophilia: relations with source of medical care. The Hemophilia Surveillance System Project Investigators. Blood 2000; 96:437.
  16. www2a.cdc.gov/ncbddd/htcweb/index.asp (Accessed on September 02, 2008).
  17. Hoots WK. Emergency management in hemophilia. In: Textbook of Hemophilia, 2nd ed, Lee CA, Berntorp EE, Hoots WK (Eds), Wiley-Blackwell, Oxford, UK 2010. p.394.
  18. Gilchrist GS, Piepgras DG, Roskos RR. Neurologic Complications in Hemophilia. In: Hemophilia in the Child and Adult, Hilgartner MW, Pochedly C (Eds), Raven Press, New York 1989. p.45.
  19. Kisker CT, Burke C. Double-blind studies on the use of steroids in the treatment of acute hemarthrosis in patients with hemophilia. N Engl J Med 1970; 282:639.
  20. Aledort LM, Haschmeyer RH, Pettersson H. A longitudinal study of orthopaedic outcomes for severe factor-VIII-deficient haemophiliacs. The Orthopaedic Outcome Study Group. J Intern Med 1994; 236:391.
  21. Saris DB, van Rinsum AC, Dhert WJ, et al. Periarticular aneurysm formation in haemophilia. Lancet 1997; 349:766.
  22. Mauser-Bunschoten EP, Zijl JA, Mali W, et al. Successful treatment of severe bleeding in hemophilic target joints by selective angiographic embolization. Blood 2005; 105:2654.
  23. Paton RW, Evans DI. Silent avascular necrosis of the femoral head in haemophilia. J Bone Joint Surg Br 1988; 70:737.
  24. Rose EH, Aledort LM. Nasal spray desmopressin (DDAVP) for mild hemophilia A and von Willebrand disease. Ann Intern Med 1991; 114:563.
  25. Franchini M, Favaloro EJ, Lippi G. Mild hemophilia A. J Thromb Haemost 2010; 8:421.
  26. Mannucci PM, Ruggeri ZM, Pareti FI, Capitanio A. 1-Deamino-8-d-arginine vasopressin: a new pharmacological approach to the management of haemophilia and von Willebrands' diseases. Lancet 1977; 1:869.
  27. Hemophilia and von Willebrand's disease: 2. Management. Association of Hemophilia Clinic Directors of Canada. CMAJ 1995; 153:147.
  28. Revel-Vilk S, Blanchette VS, Sparling C, et al. DDAVP challenge tests in boys with mild/moderate haemophilia A. Br J Haematol 2002; 117:947.
  29. Nolan B, White B, Smith J, et al. Desmopressin: therapeutic limitations in children and adults with inherited coagulation disorders. Br J Haematol 2000; 109:865.
  30. Castaman G, Mancuso ME, Giacomelli SH, et al. Molecular and phenotypic determinants of the response to desmopressin in adult patients with mild hemophilia A. J Thromb Haemost 2009; 7:1824.
  31. Sutor AH. DDAVP is not a panacea for children with bleeding disorders. Br J Haematol 2000; 108:217.
  32. Lethagen S, Harris AS, Sjörin E, Nilsson IM. Intranasal and intravenous administration of desmopressin: effect on F VIII/vWF, pharmacokinetics and reproducibility. Thromb Haemost 1987; 58:1033.
  33. Dunn AL, Powers JR, Ribeiro MJ, et al. Adverse events during use of intranasal desmopressin acetate for haemophilia A and von Willebrand disease: a case report and review of 40 patients. Haemophilia 2000; 6:11.
  34. Mannucci PM, Bettega D, Cattaneo M. Patterns of development of tachyphylaxis in patients with haemophilia and von Willebrand disease after repeated doses of desmopressin (DDAVP). Br J Haematol 1992; 82:87.
  35. Djulbegovic B, Marasa M, Pesto A, et al. Safety and efficacy of purified factor IX concentrate and antifibrinolytic agents for dental extractions in hemophilia B. Am J Hematol 1996; 51:168.
  36. Stajcić Z. The combined local/systemic use of antifibrinolytics in hemophiliacs undergoing dental extractions. Int J Oral Surg 1985; 14:339.
  37. Mannucci PM. The choice of plasma-derived clotting factor concentrates. Baillieres Clin Haematol 1996; 9:273.
  38. Lusher JM. Recombinant clotting factor concentrates. Baillieres Clin Haematol 1996; 9:291.
  39. Klein HG, Dodd RY, Dzik WH, et al. Current status of solvent/detergent-treated frozen plasma. Transfusion 1998; 38:102.
  40. Mannucci PM, Mancuso ME, Santagostino E. How we choose factor VIII to treat hemophilia. Blood 2012; 119:4108.
  41. Seremetis SV, Aledort LM, Bergman GE, et al. Three-year randomised study of high-purity or intermediate-purity factor VIII concentrates in symptom-free HIV-seropositive haemophiliacs: effects on immune status. Lancet 1993; 342:700.
  42. Giles AR, Rivard GE, Teitel J, Walker I. Surveillance for factor VIII inhibitor development in the Canadian Hemophilia A population following the widespread introduction of recombinant factor VIII replacement therapy. Transfus Sci 1998; 19:139.
  43. Calvez T, Chambost H, Claeyssens-Donadel S, et al. Recombinant factor VIII products and inhibitor development in previously untreated boys with severe hemophilia A. Blood 2014; 124:3398.
  44. Collins PW, Palmer BP, Chalmers EA, et al. Factor VIII brand and the incidence of factor VIII inhibitors in previously untreated UK children with severe hemophilia A, 2000-2011. Blood 2014; 124:3389.
  45. http://www.hemophilia.org/NHFWeb/Resource/StaticPages/menu0/menu5/menu57/masac190tables.pdf.
  46. Bray GL, Gomperts ED, Courter S, et al. A multicenter study of recombinant factor VIII (recombinate): safety, efficacy, and inhibitor risk in previously untreated patients with hemophilia A. The Recombinate Study Group. Blood 1994; 83:2428.
  47. Seremetis S, Lusher JM, Abildgaard CF, et al. Human recombinant DNA-derived antihaemophilic factor (factor VIII) in the treatment of haemophilia A: conclusions of a 5-year study of home therapy. The KOGENATE Study Group. Haemophilia 1999; 5:9.
  48. Azzi A, De Santis R, Morfini M, et al. TT virus contaminates first-generation recombinant factor VIII concentrates. Blood 2001; 98:2571.
  49. Ingerslev J, Christiansen K, Ravn HB, et al. Antibodies to heterologous proteins in hemophilia A patients receiving recombinant factor VIII (Recombinate). Thromb Haemost 2002; 87:626.
  50. Abshire TC, Brackmann HH, Scharrer I, et al. Sucrose formulated recombinant human antihemophilic factor VIII is safe and efficacious for treatment of hemophilia A in home therapy--International Kogenate-FS Study Group. Thromb Haemost 2000; 83:811.
  51. Berntorp E. Second generation, B-domain deleted recombinant factor VIII. Thromb Haemost 1997; 78:256.
  52. Sandberg H, Almstedt A, Brandt J, et al. Structural and functional characterization of B-domain deleted recombinant factor VIII. Semin Hematol 2001; 38:4.
  53. Fijnvandraat K, Berntorp E, ten Cate JW, et al. Recombinant, B-domain deleted factor VIII (r-VIII SQ): pharmacokinetics and initial safety aspects in hemophilia A patients. Thromb Haemost 1997; 77:298.
  54. Charlebois TS, O'connell BD, Adamson SR, et al. Viral safety of B-domain deleted recombinant factor VIII. Semin Hematol 2001; 38:32.
  55. Négrier C, Shapiro A, Berntorp E, et al. Surgical evaluation of a recombinant factor VIII prepared using a plasma/albumin-free method: efficacy and safety of Advate in previously treated patients. Thromb Haemost 2008; 100:217.
  56. Blanchette VS, Shapiro AD, Liesner RJ, et al. Plasma and albumin-free recombinant factor VIII: pharmacokinetics, efficacy and safety in previously treated pediatric patients. J Thromb Haemost 2008; 6:1319.
  57. Dumont JA, Liu T, Low SC, et al. Prolonged activity of a recombinant factor VIII-Fc fusion protein in hemophilia A mice and dogs. Blood 2012; 119:3024.
  58. Powell JS, Josephson NC, Quon D, et al. Safety and prolonged activity of recombinant factor VIII Fc fusion protein in hemophilia A patients. Blood 2012; 119:3031.
  59. Mahlangu J, Powell JS, Ragni MV, et al. Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A. Blood 2014; 123:317.
  60. http://www.eloctate.com/pdfs/full-prescribing-information.pdf (Accessed on June 10, 2014).
  61. Baru M, Carmel-Goren L, Barenholz Y, et al. Factor VIII efficient and specific non-covalent binding to PEGylated liposomes enables prolongation of its circulation time and haemostatic efficacy. Thromb Haemost 2005; 93:1061.
  62. Spira J, Plyushch O, Andreeva T, et al. Safety and efficacy of a long-acting liposomal formulation of plasma-derived factor VIII in haemophilia A patients. Br J Haematol 2012; 158:149.
  63. Mei B, Pan C, Jiang H, et al. Rational design of a fully active, long-acting PEGylated factor VIII for hemophilia A treatment. Blood 2010; 116:270.
  64. Saenko EL, Pipe SW. Strategies towards a longer acting factor VIII. Haemophilia 2006; 12 Suppl 3:42.
  65. Agersø H, Stennicke HR, Pelzer H, et al. Pharmacokinetics and pharmacodynamics of turoctocog alfa and N8-GP in haemophilia A dogs. Haemophilia 2012; 18:941.
  66. Schaub RG. Recent advances in the development of coagulation factors and procoagulants for the treatment of hemophilia. Biochem Pharmacol 2011; 82:91.
  67. Lindhout T, Iqbal U, Willis LM, et al. Site-specific enzymatic polysialylation of therapeutic proteins using bacterial enzymes. Proc Natl Acad Sci U S A 2011; 108:7397.
  68. White GC 2nd, Roberts HR, Kingdon HS, Lundblad RL. Prothrombin complex concentrates: potentially thrombogenic materials and clues to the mechanism of thrombosis in vivo. Blood 1977; 49:159.
  69. Kim HC, McMillan CW, White GC, et al. Purified factor IX using monoclonal immunoaffinity technique: clinical trials in hemophilia B and comparison to prothrombin complex concentrates. Blood 1992; 79:568.
  70. Roberts HR, Eberst ME. Current management of hemophilia B. Hematol Oncol Clin North Am 1993; 7:1269.
  71. White G, Shapiro A, Ragni M, et al. Clinical evaluation of recombinant factor IX. Semin Hematol 1998; 35:33.
  72. Roth DA, Kessler CM, Pasi KJ, et al. Human recombinant factor IX: safety and efficacy studies in hemophilia B patients previously treated with plasma-derived factor IX concentrates. Blood 2001; 98:3600.
  73. Shapiro AD, Di Paola J, Cohen A, et al. The safety and efficacy of recombinant human blood coagulation factor IX in previously untreated patients with severe or moderately severe hemophilia B. Blood 2005; 105:518.
  74. Windyga J, Lissitchkov T, Stasyshyn O, et al. Pharmacokinetics, efficacy and safety of BAX326, a novel recombinant factor IX: a prospective, controlled, multicentre phase I/III study in previously treated patients with severe (FIX level <1%) or moderately severe (FIX level ≤2%) haemophilia B. Haemophilia 2014; 20:15.
  75. Poon MC, Aledort LM, Anderle K, et al. Comparison of the recovery and half-life of a high-purity factor IX concentrate with those of a factor IX complex concentrate. Factor IX Study Group. Transfusion 1995; 35:319.
  76. http://www.baxter.com/downloads/healthcare_professionals/products/RIXUBIS_PI.pdf (Accessed on July 18, 2013).
  77. http://www.baxter.com/downloads/healthcare_professionals/products/RIXUBIS_PI.pdf (Accessed on July 23, 2013).
  78. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm391037.htm (Accessed on April 01, 2014).
  79. http://www.alprolix.com/pdfs/PrescribingInformation.pdf (Accessed on April 01, 2014).
  80. Peters RT, Low SC, Kamphaus GD, et al. Prolonged activity of factor IX as a monomeric Fc fusion protein. Blood 2010; 115:2057.
  81. Shapiro AD, Ragni MV, Valentino LA, et al. Recombinant factor IX-Fc fusion protein (rFIXFc) demonstrates safety and prolonged activity in a phase 1/2a study in hemophilia B patients. Blood 2012; 119:666.
  82. Powell JS, Pasi KJ, Ragni MV, et al. Phase 3 study of recombinant factor IX Fc fusion protein in hemophilia B. N Engl J Med 2013; 369:2313.
  83. http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/UCM489301.pdf (Accessed on March 17, 2016).
  84. Santagostino E, Martinowitz U, Lissitchkov T, et al. Long-acting recombinant coagulation factor IX albumin fusion protein (rIX-FP) in hemophilia B: results of a phase 3 trial. Blood 2016; 127:1761.
  85. Santagostino E, Negrier C, Klamroth R, et al. Safety and pharmacokinetics of a novel recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in hemophilia B patients. Blood 2012; 120:2405.
  86. Martinowitz U, Lubetsky A. Phase I/II, open-label, multicenter, safety, efficacy and PK study of a recombinant coagulation factor IX albumin fusion protein (rIX-FP) in subjects with hemophilia B. Thromb Res 2013; 131 Suppl 2:S11.
  87. Collins PW, Møss J, Knobe K, et al. Population pharmacokinetic modeling for dose setting of nonacog beta pegol (N9-GP), a glycoPEGylated recombinant factor IX. J Thromb Haemost 2012; 10:2305.
  88. Østergaard H, Bjelke JR, Hansen L, et al. Prolonged half-life and preserved enzymatic properties of factor IX selectively PEGylated on native N-glycans in the activation peptide. Blood 2011; 118:2333.
  89. Negrier C, Knobe K, Tiede A, et al. Enhanced pharmacokinetic properties of a glycoPEGylated recombinant factor IX: a first human dose trial in patients with hemophilia B. Blood 2011; 118:2695.
  90. Collins PW, Young G, Knobe K, et al. Recombinant long-acting glycoPEGylated factor IX in hemophilia B: a multinational randomized phase 3 trial. Blood 2014; 124:3880.
  91. Saulnier J, Marey A, Horellou MH, et al. Evaluation of desmopressin for dental extractions in patients with hemostatic disorders. Oral Surg Oral Med Oral Pathol 1994; 77:6.
  92. Lee CA, Owens D, Bray G, et al. Pharmacokinetics of recombinant factor VIII (recombinate) using one-stage clotting and chromogenic factor VIII assay. Thromb Haemost 1999; 82:1644.
  93. Schulman S, Varon D, Keller N, et al. Monoclonal purified F VIII for continuous infusion: stability, microbiological safety and clinical experience. Thromb Haemost 1994; 72:403.
  94. Martinowitz UP, Schulman S. Continuous infusion of factor concentrates: review of use in hemophilia A and demonstration of safety and efficacy in hemophilia B. Acta Haematol 1995; 94 Suppl 1:35.
  95. Hay CR, Doughty HI, Savidge GF. Continuous infusion of factor VIII for surgery and major bleeding. Blood Coagul Fibrinolysis 1996; 7 Suppl 1:S15.
  96. Schulman S, Wallensten R, White B, Smith OP. Efficacy of a high purity, chemically treated and nanofiltered factor IX concentrate for continuous infusion in haemophilia patients undergoing surgery. Haemophilia 1999; 5:96.
  97. Henrard S, Speybroeck N, Hermans C. Body weight and fat mass index as strong predictors of factor VIII in vivo recovery in adults with hemophilia A. J Thromb Haemost 2011; 9:1784.
  98. Srivastava A. Dose and response in haemophilia--optimization of factor replacement therapy. Br J Haematol 2004; 127:12.
  99. Ljung RC. Prophylactic treatment in Sweden--overtreatment or optimal model? Haemophilia 1998; 4:409.
  100. Collins PW, Blanchette VS, Fischer K, et al. Break-through bleeding in relation to predicted factor VIII levels in patients receiving prophylactic treatment for severe hemophilia A. J Thromb Haemost 2009; 7:413.
  101. Löfqvist T, Nilsson IM, Berntorp E, Pettersson H. Haemophilia prophylaxis in young patients--a long-term follow-up. J Intern Med 1997; 241:395.
  102. Petrini P, Lindvall N, Egberg N, Blombäck M. Prophylaxis with factor concentrates in preventing hemophilic arthropathy. Am J Pediatr Hematol Oncol 1991; 13:280.
  103. Valentino LA, Mamonov V, Hellmann A, et al. A randomized comparison of two prophylaxis regimens and a paired comparison of on-demand and prophylaxis treatments in hemophilia A management. J Thromb Haemost 2012; 10:359.
  104. van den Berg HM, Fischer K, Mauser-Bunschoten EP, et al. Long-term outcome of individualized prophylactic treatment of children with severe haemophilia. Br J Haematol 2001; 112:561.
  105. Gringeri A, Lundin B, von Mackensen S, et al. A randomized clinical trial of prophylaxis in children with hemophilia A (the ESPRIT Study). J Thromb Haemost 2011; 9:700.
  106. Manco-Johnson MJ, Abshire TC, Shapiro AD, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med 2007; 357:535.
  107. Lusher JM. Prophylaxis in children with hemophilia: is it the optimal treatment? Thromb Haemost 1997; 78:726.
  108. Hemophilia Information Exchange: Medical and Scientific Advisory Council (MASAC) recommendations concerning prophylaxis. Med Bulletin #197, March 11,1994.
  109. Richards M, Williams M, Chalmers E, et al. A United Kingdom Haemophilia Centre Doctors' Organization guideline approved by the British Committee for Standards in Haematology: guideline on the use of prophylactic factor VIII concentrate in children and adults with severe haemophilia A. Br J Haematol 2010; 149:498.
  110. Journeycake JM, Quinn CT, Miller KL, et al. Catheter-related deep venous thrombosis in children with hemophilia. Blood 2001; 98:1727.
  111. Ljung R. The risk associated with indwelling catheters in children with haemophilia. Br J Haematol 2007; 138:580.
  112. Astermark J, Petrini P, Tengborn L, et al. Primary prophylaxis in severe haemophilia should be started at an early age but can be individualized. Br J Haematol 1999; 105:1109.
  113. Fischer K, van der Bom JG, Mauser-Bunschoten EP, et al. The effects of postponing prophylactic treatment on long-term outcome in patients with severe hemophilia. Blood 2002; 99:2337.
  114. Kreuz W, Escuriola-Ettingshausen C, Funk M, et al. When should prophylactic treatment in patients with haemophilia A and B start?--The German experience. Haemophilia 1998; 4:413.
  115. van Dijk K, Fischer K, van der Bom JG, et al. Can long-term prophylaxis for severe haemophilia be stopped in adulthood? Results from Denmark and the Netherlands. Br J Haematol 2005; 130:107.
  116. Collins P, Faradji A, Morfini M, et al. Efficacy and safety of secondary prophylactic vs. on-demand sucrose-formulated recombinant factor VIII treatment in adults with severe hemophilia A: results from a 13-month crossover study. J Thromb Haemost 2010; 8:83.
  117. Raffini L, Manno C. Modern management of haemophilic arthropathy. Br J Haematol 2007; 136:777.
  118. Jansen NW, Roosendaal G, Lafeber FP. Understanding haemophilic arthropathy: an exploration of current open issues. Br J Haematol 2008; 143:632.
  119. Siegel ME, Siegel HJ, Luck JV Jr. Radiosynovectomy's clinical applications and cost effectiveness: a review. Semin Nucl Med 1997; 27:364.
  120. Triantafyllou SJ, Hanks GA, Handal JA, Greer RB 3rd. Open and arthroscopic synovectomy in hemophilic arthropathy of the knee. Clin Orthop Relat Res 1992; :196.
  121. Dunn AL, Busch MT, Wyly JB, Abshire TC. Radionuclide synovectomy for hemophilic arthropathy: a comprehensive review of safety and efficacy and recommendation for a standardized treatment protocol. Thromb Haemost 2002; 87:383.
  122. Rodriguez-Merchan EC. Therapeutic options in the management of articular contractures in haemophiliacs. Haemophilia 1999; 5 Suppl 1:5.
  123. Schick M, Stucki G, Rodriguez M, et al. Haemophilic; arthropathy: assessment of quality of life after total knee arthroplasty. Clin Rheumatol 1999; 18:468.
  124. Nelson IW, Sivamurugan S, Latham PD, et al. Total hip arthroplasty for hemophilic arthropathy. Clin Orthop Relat Res 1992; :210.
  125. Luck JV Jr, Kasper CK. Surgical management of advanced hemophilic arthropathy. An overview of 20 years' experience. Clin Orthop Relat Res 1989; :60.
  126. Solimeno LP, Mancuso ME, Pasta G, et al. Factors influencing the long-term outcome of primary total knee replacement in haemophiliacs: a review of 116 procedures at a single institution. Br J Haematol 2009; 145:227.
  127. Rodriguez-Merchan EC. Orthopaedic surgery in persons with haemophilia. Thromb Haemost 2003; 89:34.
  128. Tagariello G, Iorio A, Santagostino E, et al. Comparison of the rates of joint arthroplasty in patients with severe factor VIII and IX deficiency: an index of different clinical severity of the 2 coagulation disorders. Blood 2009; 114:779.
  129. Soucie JM, Cianfrini C, Janco RL, et al. Joint range-of-motion limitations among young males with hemophilia: prevalence and risk factors. Blood 2004; 103:2467.
  130. Goedert JJ, Eyster ME, Lederman MM, et al. End-stage liver disease in persons with hemophilia and transfusion-associated infections. Blood 2002; 100:1584.
  131. Horowitz B, Bonomo R, Prince AM, et al. Solvent/detergent-treated plasma: a virus-inactivated substitute for fresh frozen plasma. Blood 1992; 79:826.
  132. Lee CA. Transfusion-transmitted disease. Baillieres Clin Haematol 1996; 9:369.
  133. Santagostino E, Mannucci PM, Gringeri A, et al. Transmission of parvovirus B19 by coagulation factor concentrates exposed to 100 degrees C heat after lyophilization. Transfusion 1997; 37:517.
  134. Morfini M, Longo G, Rossi Ferrini P, et al. Hypoplastic anemia in a hemophiliac first infused with a solvent/detergent treated factor VIII concentrate: the role of human B19 parvovirus. Am J Hematol 1992; 39:149.
  135. Eyster ME, Diamondstone LS, Lien JM, et al. Natural history of hepatitis C virus infection in multitransfused hemophiliacs: effect of coinfection with human immunodeficiency virus. The Multicenter Hemophilia Cohort Study. J Acquir Immune Defic Syndr 1993; 6:602.
  136. Lesens O, Deschênes M, Steben M, et al. Hepatitis C virus is related to progressive liver disease in human immunodeficiency virus-positive hemophiliacs and should be treated as an opportunistic infection. J Infect Dis 1999; 179:1254.
  137. Tradati F, Colombo M, Mannucci PM, et al. A prospective multicenter study of hepatocellular carcinoma in italian hemophiliacs with chronic hepatitis C. The Study Group of the Association of Italian Hemophilia Centers. Blood 1998; 91:1173.
  138. Darby SC, Ewart DW, Giangrande PL, et al. Mortality from liver cancer and liver disease in haemophilic men and boys in UK given blood products contaminated with hepatitis C. UK Haemophilia Centre Directors' Organisation. Lancet 1997; 350:1425.
  139. Fried MW. Management of hepatitis C in the hemophilia patient. Am J Med 1999; 107:85S.
  140. Gordon FH, Mistry PK, Sabin CA, Lee CA. Outcome of orthotopic liver transplantation in patients with haemophilia. Gut 1998; 42:744.
  141. Wilde J, Teixeira P, Bramhall SR, et al. Liver transplantation in haemophilia. Br J Haematol 2002; 117:952.
  142. Plug I, Peters M, Mauser-Bunschoten EP, et al. Social participation of patients with hemophilia in the Netherlands. Blood 2008; 111:1811.
  143. Bradley CS, Bullinger M, McCusker PJ, et al. Comparing two measures of quality of life for children with haemophilia: the CHO-KLAT and the Haemo-QoL. Haemophilia 2006; 12:643.
  144. du Treil S, Rice J, Leissinger CA. Quantifying adherence to treatment and its relationship to quality of life in a well-characterized haemophilia population. Haemophilia 2007; 13:493.
  145. Pollak E, Mühlan H, VON Mackensen S, et al. The Haemo-QoL Index: developing a short measure for health-related quality of life assessment in children and adolescents with haemophilia. Haemophilia 2006; 12:384.
  146. van der Net J, Vos RC, Engelbert RH, et al. Physical fitness, functional ability and quality of life in children with severe haemophilia: a pilot study. Haemophilia 2006; 12:494.
  147. Tagliaferri A, Di Perna C, Santoro C, et al. Cancers in patients with hemophilia: a retrospective study from the Italian Association of Hemophilia Centers. J Thromb Haemost 2012; 10:90.
  148. Biron-Andreani C, de Moerloose P, D'oiron R, et al. Cancer detection and management in patients with haemophilia: a retrospective European multicentre study. Haemophilia 2014; 20:78.
  149. Anagnostis P, Vakalopoulou S, Slavakis A, et al. Reduced bone mineral density in patients with haemophilia A and B in Northern Greece. Thromb Haemost 2012; 107:545.
  150. Anagnostis P, Vakalopoulou S, Charizopoulou M, et al. Vitamin D deficiency in patients with haemophilia: an underestimated commorbidity. Haemophilia 2013; 19:e308.
  151. Linari S, Montorzi G, Bartolozzi D, et al. Hypovitaminosis D and osteopenia/osteoporosis in a haemophilia population: a study in HCV/HIV or HCV infected patients. Haemophilia 2013; 19:126.
  152. Mannucci PM, Schutgens RE, Santagostino E, Mauser-Bunschoten EP. How I treat age-related morbidities in elderly persons with hemophilia. Blood 2009; 114:5256.
  153. Franchini M, Mannucci PM. Co-morbidities and quality of life in elderly persons with haemophilia. Br J Haematol 2010; 148:522.
  154. Coppola A, Tagliaferri A, Franchini M. The management of cardiovascular diseases in patients with hemophilia. Semin Thromb Hemost 2010; 36:91.
  155. Schutgens RE, Tuinenburg A, Roosendaal G, et al. Treatment of ischaemic heart disease in haemophilia patients: an institutional guideline. Haemophilia 2009; 15:952.
  156. Lim MY, Pruthi RK. Cardiovascular disease risk factors: prevalence and management in adult hemophilia patients. Blood Coagul Fibrinolysis 2011; 22:402.
  157. Sharathkumar AA, Soucie JM, Trawinski B, et al. Prevalence and risk factors of cardiovascular disease (CVD) events among patients with haemophilia: experience of a single haemophilia treatment centre in the United States (US). Haemophilia 2011; 17:597.
  158. Staritz P, de Moerloose P, Schutgens R, et al. Applicability of the European Society of Cardiology guidelines on management of acute coronary syndromes to people with haemophilia - an assessment by the ADVANCE Working Group. Haemophilia 2013; 19:833.
  159. Kitazawa T, Igawa T, Sampei Z, et al. A bispecific antibody to factors IXa and X restores factor VIII hemostatic activity in a hemophilia A model. Nat Med 2012; 18:1570.
  160. Muto A, Yoshihashi K, Takeda M, et al. Anti-factor IXa/X bispecific antibody (ACE910): hemostatic potency against ongoing bleeds in a hemophilia A model and the possibility of routine supplementation. J Thromb Haemost 2014; 12:206.
  161. Muto A, Yoshihashi K, Takeda M, et al. Anti-factor IXa/X bispecific antibody ACE910 prevents joint bleeds in a long-term primate model of acquired hemophilia A. Blood 2014; 124:3165.
  162. Uchida N, Sambe T, Yoneyama K, et al. A first-in-human phase 1 study of ACE910, a novel factor VIII-mimetic bispecific antibody, in healthy subjects. Blood 2016; 127:1633.
  163. Shima M, Hanabusa H, Taki M, et al. Factor VIII-Mimetic Function of Humanized Bispecific Antibody in Hemophilia A. N Engl J Med 2016; 374:2044.
  164. https://clinicaltrials.gov/ct2/show/NCT02622321 (Accessed on May 26, 2016).
  165. Ragni MV. Targeting Antithrombin to Treat Hemophilia. N Engl J Med 2015; 373:389.
  166. Sehgal A, Barros S, Ivanciu L, et al. An RNAi therapeutic targeting antithrombin to rebalance the coagulation system and promote hemostasis in hemophilia. Nat Med 2015; 21:492.
  167. Pierce GF, Lillicrap D, Pipe SW, Vandendriessche T. Gene therapy, bioengineered clotting factors and novel technologies for hemophilia treatment. J Thromb Haemost 2007; 5:901.
  168. Nienhuis AW. Development of gene therapy for blood disorders. Blood 2008; 111:4431.
  169. Kasuda S, Kubo A, Sakurai Y, et al. Establishment of embryonic stem cells secreting human factor VIII for cell-based treatment of hemophilia A. J Thromb Haemost 2008; 6:1352.
  170. Kren BT, Unger GM, Sjeklocha L, et al. Nanocapsule-delivered Sleeping Beauty mediates therapeutic Factor VIII expression in liver sinusoidal endothelial cells of hemophilia A mice. J Clin Invest 2009; 119:2086.
  171. Aljamali MN, Margaritis P, Schlachterman A, et al. Long-term expression of murine activated factor VII is safe, but elevated levels cause premature mortality. J Clin Invest 2008; 118:1825.
  172. Margaritis P, Roy E, Aljamali MN, et al. Successful treatment of canine hemophilia by continuous expression of canine FVIIa. Blood 2009; 113:3682.
  173. Roth DA, Tawa NE Jr, O'Brien JM, et al. Nonviral transfer of the gene encoding coagulation factor VIII in patients with severe hemophilia A. N Engl J Med 2001; 344:1735.
  174. Powell JS, Ragni MV, White GC 2nd, et al. Phase 1 trial of FVIII gene transfer for severe hemophilia A using a retroviral construct administered by peripheral intravenous infusion. Blood 2003; 102:2038.
  175. Manno CS, Pierce GF, Arruda VR, et al. Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat Med 2006; 12:342.
  176. Kay MA, Manno CS, Ragni MV, et al. Evidence for gene transfer and expression of factor IX in haemophilia B patients treated with an AAV vector. Nat Genet 2000; 24:257.
  177. Manno CS, Chew AJ, Hutchison S, et al. AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe hemophilia B. Blood 2003; 101:2963.
  178. Nathwani AC, Tuddenham EG, Rangarajan S, et al. Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N Engl J Med 2011; 365:2357.
  179. Nathwani AC, Reiss UM, Tuddenham EG, et al. Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N Engl J Med 2014; 371:1994.
  180. Jiang H, Lillicrap D, Patarroyo-White S, et al. Multiyear therapeutic benefit of AAV serotypes 2, 6, and 8 delivering factor VIII to hemophilia A mice and dogs. Blood 2006; 108:107.
  181. Waddington SN, Nivsarkar MS, Mistry AR, et al. Permanent phenotypic correction of hemophilia B in immunocompetent mice by prenatal gene therapy. Blood 2004; 104:2714.
  182. Ohlfest JR, Frandsen JL, Fritz S, et al. Phenotypic correction and long-term expression of factor VIII in hemophilic mice by immunotolerization and nonviral gene transfer using the Sleeping Beauty transposon system. Blood 2005; 105:2691.
  183. Ide LM, Gangadharan B, Chiang KY, et al. Hematopoietic stem-cell gene therapy of hemophilia A incorporating a porcine factor VIII transgene and nonmyeloablative conditioning regimens. Blood 2007; 110:2855.
  184. Brown BD, Cantore A, Annoni A, et al. A microRNA-regulated lentiviral vector mediates stable correction of hemophilia B mice. Blood 2007; 110:4144.
  185. Murphy SL, High KA. Gene therapy for haemophilia. Br J Haematol 2008; 140:479.
  186. Scott DW, Lozier JN. Gene therapy for haemophilia: prospects and challenges to prevent or reverse inhibitor formation. Br J Haematol 2012; 156:295.
  187. Follenzi A, Benten D, Novikoff P, et al. Transplanted endothelial cells repopulate the liver endothelium and correct the phenotype of hemophilia A mice. J Clin Invest 2008; 118:935.
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